Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

Published date : 13 Dec 2017

Catalytic proteins such as human protein tyrosine phosphatase 1B (PTP1B), with conserved and highly polar active sites, warrant the discovery of druggable non-active sites, such as allosteric sites, and potentially, therapeutic small molecules that can bind to these sites. Catalyzing the dephosphorylation of numerous substrates, PTP1B is physiologically important in intracellular signal transduction pathways in diverse cell types and tissues. Aberrant PTP1B is associated with obesity, diabetes, cancers, and neurodegenerative disorders.

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Journal Paper
journal
Proteins: Structure, Function, and Bioinformatics, 13 Dec 2017, doi: 10.1002/prot.25440
Impact Factor
2.499

Modeling the full length HIV-1 Gag polyprotein reveals the role of its p6 subunit in viral maturation and the effect of non-cleavage site mutations in protease drug resistance

Published date : 13 Dec 2017

HIV polyprotein Gag is increasingly found to contribute to protease inhibitor resistance. Despite its role in viral maturation and in developing drug resistance, there remain gaps in the knowledge of the role of certain Gag subunits (e.g. p6), and that of non-cleavage mutations in drug resistance. As p6 is flexible, it poses a problem for structural experiments, and is hence often omitted in experimental Gag structural studies.

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Journal Paper
journal
Journal of Biomolecular Structure and Dynamics, 2017, Pg 1-40, doi: 10.1080/07391102.2017.1417160

Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma

Published date : 12 Dec 2017

Currently, molecular markers are not used when determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). In the present study, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT) and adjacent non-malignant tissues (AT) typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients.

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Journal Paper
journal
Molecular Oncology, 8 Nov 2017, doi: 10.1002/1878-0261.12153
Impact Factor
5.314

An Intramolecular Tryptophan-Condensation Approach for Peptide Stapling

Published date : 08 Dec 2017

Stapled peptides are gaining tremendous interest as next-generation therapeutic agents to target protein-protein interactions. Herein, we report an intramolecular peptide stapling method which links two tryptophan residues at C2 position of the indole moieties via acid-mediated condensation with an aldehyde.

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Journal Paper
journal
Organic & Biomolecular Chemistry, 2017, doi: 10.1039/C7OB02667F
Impact Factor
3.564

Insulin-Degrading Enzyme in the Fight against Alzheimer's Disease

Published date : 29 Nov 2017

After decades of research and clinical trials there is still no cure for Alzheimer's disease (AD). While impaired clearance of amyloid beta (Aβ) peptides is considered as one of the major causes of AD, it was recently complemented by a potential role of other toxic amyloidogenic species. Insulin-degrading enzyme (IDE) is the proteolytic culprit of various β-forming peptides, both extracellular and intracellular.

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Journal Paper
journal
Trends in Pharmacological Sciences, 10 Nov 2017, doi : 10.1016/j.tips.2017.10.008
Impact Factor
12.797

Spin-charge conversion in disordered two-dimensional electron gases lacking inversion symmetry

Published date : 20 Nov 2017

We study the spin-charge conversion mechanisms in a two-dimensional gas of electrons moving in a smooth disorder potential by accounting for both Rashba-type and Mott's skew scattering contributions. We find that the quantum interference effects between spin-flip and skew scattering give rise to anisotropic spin precession scattering (ASP), a direct spin-charge conversion mechanism that was discovered in an earlier study of graphene decorated with adatoms [Huang et al., Phys. Rev. B 94, 085414 (2016)].

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Journal Paper
journal
Physical Review B, Vol. 96, 2017, doi: 10.1103/PhysRevB.96.205305
Impact Factor
3.836

Structural analyses unravel the molecular mechanism of cyclic di-GMP regulation of bacterial chemotaxis via a PilZ adaptor protein

Published date : 16 Nov 2017

The bacterial second messenger cyclic di-GMP (c-di-GMP) has emerged as a prominent mediator of bacterial physiology, motility, and pathogenicity. c-di-GMP often regulates the function of its protein targets through a unique mechanism that involves a discrete PilZ adaptor protein. However, the molecular mechanism for PilZ protein–mediated protein regulation is unclear. Here, we present the structure of the PilZ adaptor protein MapZ cocrystallized in complex with c-di-GMP and its protein target CheR1, a chemotaxis-regulating methyltransferase in Pseudomonas aeruginosa.

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Journal Paper
journal
Journal of Biological Chemistry, 5 January 2018, 293, 1, 100-111
Impact Factor
4.125

Characterizing the Conformational Landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations

Published date : 15 Nov 2017

The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the ‘conformational selection’ paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by ‘binding induced folding’.

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Journal Paper
journal
Scientific Reports 7, Article no:15600, 2017, doi:10.1038/s41598-017-15930-4
Impact Factor
4.259

Small molecules targeting the inactive form of the Mnk 1/2 kinases

Published date : 14 Nov 2017

Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogenactivated protein kinases-interacting kinases 1 and 2 (Mnk1/2) activate the oncogene eIF4E through posttranslational modification (phosphorylating it at the conserved Ser209). Inhibition of Mnk prevents eIF4E phosphorylation, making the Mnk−eIF4E axis a potential therapeutic target for oncology. Recently, the design and synthesis of a series of novel potent compounds inhibiting the Mnk1/2 kinases were carried out in-house.

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Journal Paper
journal
ACS Omega 2017, 2, Pg 7881 - 7891, doi: 10.1021/acsomega.7b01403

A yeast two-hybrid system for the screening and characterization of small-molecule inhibitors of protein–protein interactions identifies a novel putative Mdm2-binding site in p53

Published date : 09 Nov 2017

Background: Protein–protein interactions (PPIs) are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as host-pathogen interactions and cancer cell proliferation. However, isolation of PPI inhibitors is extremely challenging. While several in vitro assays to screen for PPI inhibitors are available, they are often expensive, cumbersome, and require large amounts of purified protein. In contrast, limited in vivo assays are available to screen for small-molecule inhibitors of PPI.

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Journal Paper
journal
BMC Biology 2017 15:108, doi: 10.1186/s12915-017-0446-7
Impact Factor
6.779